DESCRIPTION (provided by candidate): Rats will suppress intake of a saccharin solution that predicts either the passive or the active (i.e., self-) administration of a drug of abuse. Initially, it was believed that drugs of abuse were producing a conditioned taste aversion, similar to that induced by the aversive agent, lithium chloride. More recent evidence, however, suggests that the supressive effects of drugs of abuse are caused by devaluation of the natural reward (i.e., the saccharin cue) in anticipation of the availability of the more potent drug reward. This phenomenon, referred to reward comparison [18], occurs in both male and female rats when the cocaine is administered passively and large individual differences in saccharin intake are evident amongst rats of each sex. The large suppressing rats show greater avoidance of the saccharin cue than do either small suppressing rats or the saline controls. When tested using iv self-administration in males, greater avoidance of the saccharin cue is highly correlated with greater cocaine self-administration [23]. Interestly, in our hands, females appear to be more resistant to cocaine-induced suppression of CS intake than males and they take less drug in this paradigm. This finding was somewhat unexpected because a substantial amount of literature shows that female rats take more drug than male rats and greater preference for the drug unconditioned stimulus (US) should be associated with more, rather than less, avoidance of the less valuable taste cue. This disjunction led us to hypothesize that the availability of the saccharin cue (even for just 5 min/day) is sufficient to reduce cocaine self-administration behavior and, moreover, that these protective effects of the sweet are greater in female than in male rats. Specific Aim 1 tests whether the availability of the saccharin cue serves to reduce acquisition and reinstatement of cocaine selfadministration and whether this effect is greater in female rats. Specific Aim 2 tests whether estrogen is required for this phenomenon. Finally, Specific Aim 3 tests whether accumbens dopamine, which tracks the comparison between natural rewards and drugs of abuse, is more sensitive in the female rat. If our predictions prove correct, the data will suggest that, while increased sensitivity to reward may predispose females to addiction in the absence of alternative natural rewards, it also may be highly protective when a valued natural reward is available.